The goal of this project is to investigate the functional neuroanatomy of cognitive and emotional processing in humans as it relates to late life depression. This Center has proposed a cerebrovascular lesion model in which small vascular lesions within prefrontal cortex, basal ganglia, and related structures lead to the development of late life depression [1,2]. Here we propose to use functional magnetic resonance imaging (fMRI) supplemented by psychophysiological recording to investigate prefrontal cortical function in emotional regulation during depression. We have adopted as our framework Mayberg?s model delineating the role of prefrontal cortex in depression [3]. Mayberg proposed that three brain systems comprise the neurological substrate of depression: (1) a dorsal attention-cognitive system composed of dorsolateral prefrontal cortex (PFC) (Brodmann areas, BA 9/46,44), the anterior cingulate (BA 24), and inferior parietal cortex (BA 40), (2) a ventral vegetative-somatic system composed of ventral frontal (BA 47) cortex, the amygdala, hippocampus, subgenual cingulate (BA 25), and ventral insula and (3) a rostral cingulate region (BA 24) that integrates the dorsal and ventral systems. A reciprocal relationship between the dorsal and ventral system is believed to regulate mood. Sadness and depression are associated with decreased activity in the dorsal system and increased activity in the ventral system. Remission of depression reverses these relationships. We will test this model in the context of the vascular lesion model proposed above. There are four specific aims: (1) we will investigate the interplay between dorsal and ventral brain systems in-patients with late life depression and MRI-verified prefrontal lesions, and in age-matched controls with no lesions or depression. We will use a target detection task to engage dorsolateral prefrontal cortex with embedded task-irrelevant neutral and emotional distracters to engage ventral prefrontal cortex and the amygdala. (2) We will compare the pattern of functional activation found in patients with late life depression and prefrontal lesions with age-matched controls who have had a sad mood induced by an experimental Relived Emotion procedure. (3) We will compare the pattern of functional activation found in patients with late life depression and prefrontal lesions after treatment. (4) We will investigate the time course of habituation for stimuli with emotional valence and the salience for conditioned emotional stimuli using fMRI supplemented by psychophysiological measurement.